Fatal cerebral edema often complicates treatment of diabetic ketoacidosis (DKA); the etiology is unknown. Experimental DKA was induced in alloxan diabetic rabbits by IV infusion of Beta- hydroxybutyric acid (BOHBA) for 4-6 hrs, keeping plasma BOHBA at 15 mM, with blood pH equals 7.10, HCO3 equal 9 mEq/L and glucose equal 25 mM. Measurements were made of blood, pH, pO2, pCO2 and of concentrations of Na, K, Cl, glucose, lactate, H2O, osmoles and BOHBA in plasma, CSF and brain, before and after treatment with either insulin or HCO minus 3. After 4 hours of BOHBA infusion, there were significant increases in brain content of H2O (5%), Na (9%), K (4%) and Cl (6%), but after 6 hours, brain H2O and electrolytes were normal. Lowering plasma glucose with insulin from 25 to 18 mM had no effect, but when glucose was lowered to 9 mM, there was brain edema, with increased brain content of H2O (13%) and osmoles (13%), but brain content of Na, K, Cl, glucose, lactate and BOHBA were normal, and osmolality of CSF, brain and plasma (290 mOsm/kg H2O) were similar. Other animals received Na HCO3 infusion, without insulin, to rapidly raise plasma HCO3 from 9 to 21 mEq/L. There was no brain edema, brain solutes were normal, and brain, plasma and CSF osmolality were similar (310 mOsm/kg H2O). The data suggest that ketoacidosis, per se, induces transient brain edema, possibly related coma associated with clinical DKA. Rapid lowering of plasma glucose with insulin can produce cerebral edema when glucose falls below 10 mM, but without insulin, rapid correction of acidosis with HCO minus 3 does not appear to produce brain edema.